It is common practice to synthesize and market a drug possessing a chiral center as its racemate. If an enantiomerically pure molecule is needed, one often synthesizes the racemate and then chirally separates the enantiomers. Manufacturing racemates means that a quantity of compound contains an equivalent weight (approximately) of isomers, one of which often has no therapeutic value and potentially may cause unsuspected side effects. For example, the sedative thalidomide was marketed as a racemate. Sedative activity resided in the R-isomer, but the contaminating S-isomer is a teratogen and is thought to cause birth defects in babies born to mothers using this drug. The R,R-enantiomer of the tuberculostatic Ethambutol can cause blindness. The lethal side effects associated with the nonsteroidal anti-inflammatory drag benoxaprofen (Oraflex) might have been avoided had the drug been sold as a pure enantiomer.
However, the issue of enantiomeric purity is not limited to the field of pharmaceuticals. For example, ASANA (.sup.i Pr=isopropyl) is a synthetic pyrethroid insecticide which contains two asymmetric centers. The potent insecticidal activity resides overwhelmingly in just one of four possible stereoisomers. Moreover, the three non-insecticidal stereoisomers exhibit cytotoxicity in certain plant species. Therefore, ASANA can only be sold as a single stereoisomer because the mixed stereoisomers would not be suitable. Therefore, there is a need to manufacture certain compounds with at least one chiral center as pure specific enantiomeric compounds and not as a racemate.
The pharmaceutical compound (R)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine (described in WO93/17684, and in U.S. patent application 08/307,554, filed Sep. 16, 1994, the disclosure of which is incorporated in its entirety by reference herein) is useful for a wide variety of therapeutic indications, including, for example, sepsis and sepsis syndrome, trauma, increasing the production of multilineage cells after cytoreductive therapies, promoting engraftment after bone marrow transplantation, and alleviating the toxic side effect of interleukin-2 (IL-2), amphotericin B, cyclosporin A or FK506 therapy and granulocyte macrophage colony stimulating factor (GM-CSF) therapy. The synthesis procedure described in the foregoing International and U.S. Patent Applications is capable of achieving a chiral purity of about 95% for the R enantiomer. Also, the process disclosed has limited application for producing larger quantities of product. Therefore, there is a need in the art to improve upon this commercially viable synthetic process for producing a compound of higher enantiomeric purity.
Large-scale manufacturing of synthetic compounds, particularly compounds having a high enantiomeric purity, is usually not a simple process of increasing reagent quantitites or reaction vessel volumes. In fact, often the scale-up of synthetic protocols results in unexpected and undesirable results and/or contaminants, failing to provide commercially viable manufacturing methods. The invention addresses this need, providing a less expensive synthetic process utilizing readily available (or readily prepared) starting materials. The inventive process is directed to synthetic procedures for preparing products and isolating certain intermediates in significantly larger quantities with far higher yields and greater purity, being heretofore unknown.
Others have described synthetic processes for making chiral enantiomers using stereo specific routes involving catalytic activation, one such process is discussed in Lampilas et al., "Convergent Stereospecific Total Synthesis of Monochiral Monocillin I Related Macrolides," Tetrahedran Letters, Vol. 33, No. 6, pp. 777-780 (1992). However, Lampilas et al. is limited to reacting R (or S) propylene oxide with a lithium salt of a branched alkoxyalkynyl and subsequent preparation of a primary alcohol used in successive synthetic steps to obtain the disclosed monochiral Monocillin I and corresponding derivatives.
Mori et al., "Synthesis of the Enantiomers of cis-2-Methyl-5-Hexanolide, the Major Component of the Sex Pheromone of the Carpenter Bee," Tetrahedron, vol. 41, No.3, pp. 541-546 (1985), discloses synthesis of bichiral (2R,5S)-2-Methyl-5-hexanolide from an ethyl (2)-lactate starting material. Using a published process for preparing (S-)-propylene oxide, Mori et al. discloses converting an intermediate ester product to the corresponding (R-)-propylene oxide, having an optically determined enantiomeric purity of 97.3%. Mori et al. is limited to preparing the disclosed pheromone via the propylene oxide intermediate.
Johnston et al., "Facile Syntheses of the Enantiomers of Sulcatol," Can. J. Chem., vol. 75, pp. 233-235 (1979), discloses a synthesis for an aggregation pheromone, Sulcatol, prepared from methyl oxirane enantiomers. The R-(+)-methyl oxirane was prepared from S-(-)-ethyllactate, first converting it to tosylate and subsequently reacting the tosylate to obtain a the corresponding oxirane. The disclosed tosylate yield is 71% (based on a lactate starting material) and the resulting methyloxirane was obtained in a disclosed 50% yield (based on tosylate starting material). Johnston et al. specifically requires depressed reaction temperatures and very long reaction times (8 days). Johnston et al. is limited to specific process conditions that are non-scalable for commercial purposes and that require reaction conditions not embraced in the inventive synthetic procedure for preparing chiral propylene oxide.
Hillis et al,. "Improved Preparation of (+)-(R)-Methyloxirane," J. Org. Chem., vol. 46, pp. 3349-3352 (1981), disclose processes for preparing (+)-R-methyloxirane from (+)-(S)-lactate in several process steps. In the disclosed process steps, methanesulfonyl chloride was allowed to react with the lactate starting material in toluene, producing an intermediate, ethyl (-)-(S)-2-(mesyloxy)propanoate. The intermediate was then reacted with LiAlH.sub.4 in THF, resulting in an alcohol precursor. The alcohol precusor was reacted in a distillation process with KOH to obtain the desired oxirane product. Hillis et al. is limited to a process for obtaining the disclosed oxirane product via the specific steps provided. Hillis et al. do not disclose a method for preparing chiral secondary alcohols or derivatives thereof. Furthermore, the disclosed process for preparing the oxirane products is not the inventive process. The disclosed process requires formation of a sulfonyl intermediate and distillation of a final product, the latter of which is particularly unadaptable for commercial preparation.
Ellis et al., "Optically Active Epoxides from Vicinal Diols via Vicinal Acetoxy Bromides: The Enantiomeric Methyl oxiranes," Org. Syn., vol. 63, pp. 140-145 (1984), discloses synthetic protocols for preparing S-(-)-methyloxirane from ethyl-L-(-)-lactate through esterification, halogenation and corresponding reduction reactions. Disclosed yields for the propylene oxide intermediate are substantially less than the yields permitted by the inventive method. The disclosed synthesis requires reducing the lactate ester using lithium aluminum hydride, followed by simultaneously esterifying and halogenating an intermediate diol.
The process disclosed in Ellis et al. is limited to the specifc synthetic steps disclosed. These disclosed steps differ from the inventive process in that they do not disclose preparing R-(+)-propylene oxide via the inventive process or subsequently reacting in the R-(+)-propylene oxide in a series of reactions to obtain a secondary chiral alcohol.
Nokami et al., "A New Approach to the Synthesis of .alpha.-Hydroxy-.alpha.,.beta.-unsaturated Macrolides and (-)-Pyrenophorin...", Chem. Letters, pp. 1103-1106 (1994), discloses a process for preparing (+)- and (-)-Pyrenophorin, in which a first process step includes treating S-(-)-propylene oxide with lithium 3-tetrahydropyranyloxypropynylide to obtain an optically active alcohol. The resulting alcohol is converted to a corresponding benzl ether, and the THP-ether hydrolyzed to the corresponding alcohol. Other resulting intermediates are prepared in sequential synthetic steps to obtain a final product, (+)-/(-)-pyrenophorin. Nokami et al. is limited to preparing S-(-)-propylene oxide and other intermediates in process steps different than permitted by the inventive process to obtain a chemically different product from compounds produced by the inventive process.
The inventive process therefore provides a heretofore unknown method for preparing chiral secondary alcohols and selectively preparing and isolating intermediates thereof. The process addresses known, commercially-limiting process steps, including restrictive and unscalable reaction conditions, undesireable yields and by product contamination of desired products.